The principle investigator in this proposal, John Kuluz, MD, is a pediatric intensivist at the University of Miami School of Medicine who regularly cares for a large number of infants, children and adolescents with a variety of acute and chronic brain injuries. His dedication to improving the neurologic outcome of patients following ischemic and traumatic brain injury has motivated him to investigate important questions related to the care of these children in the basic science research laboratory of the Division of Pediatric Critical Care Medicine. However, Dr. Kuluz lacks formal training in neuroscience research methods and therefore has not been capable of designing and performing experiments aimed at uncovering the scientific mechanisms underlying his observations using his current elementary abilities. The broad, long-term objective of this proposal is to train this young clinician-scientist in a large number of basic science research methods and techniques, under the direct supervision of established senior investigators, so that he can embark of a full and productive research career, designing and completing future studies aimed at improving neurological outcome of brain-injured children. Disturbances in thermoregulation resulting in elevated temperature occur commonly after acute brain injury in humans and may delay or even impede neurologic recovery. The principle investigator has previously identified a robust thermoregulatory response to middle cerebral artery occlusion (MCAO) in rats, which result results in marked elevations in both rectal and brain temperature during and after the ischemic period. This phenomenon is rats appears to mimic the thermoregulatory response of humans to ischemic and traumatic brain injury. The major goal of this project is to enhance our understanding of the mechanisms and functional significance of the thermoregulatory response to focal brain ischemia in rats so that neurologic outcome following brain injury in humans can be maximized. The scientific goal of these experiments is to determine the endogenous pyrogen which is responsible for the increase in temperature during MCAO and whether this pyrogen plays a deleterious role in the pathogenesis of focal cerebral ischemia-reperfushion injury. Specific aims are: (1) to measure the changes in brain and body temperature during and for 3 days and up to 30 days after MCAO; (2) to measure the changes in regional cerebral blood flow during MCAO before and after the rise in temperature; (3) to determine the regional distribution, cellular origin(s) and temporal profile of synthesis of the responsible endogenous pyrogen during and after MCAO; and (4) to determine the role of the pyrogen in the thermoregulatory response to MCAO and whether the effects of this pyrogen on focal cerebral ischemia-reperfushion injury are temperature-dependent.